Unnatural amino acid analogues of membrane-active helical peptides with anti-mycobacterial activity and improved stability

Objectives The emergence of MDR-TB, coupled with shrinking antibiotic pipelines, has increased demands for new antimicrobials with novel mechanisms of action. Antimicrobial peptides have increasingly been explored as promising alternatives to antibiotics, but their inherent poor in vivo stability remains an impediment to their clinical utility. We therefore systematically evaluated unnatural amino acid-modified peptides to design analogues with enhanced anti-mycobacterial activities. Methods Anti-mycobacterial activities were evaluated in vitro and intracellularly against drug-susceptible and MDR isolates of Mycobacterium tuberculosis using MIC, killing efficacy and intracellular growth inhibition studies. Toxicity profiles were assessed against mammalian cells to verify cell selectivity. Anti-mycobacterial mechanisms were investigated using microfluidic live-cell imaging with time-lapse fluorescence microscopy and confocal laser-scanning microscopy. Results Unnatural amino acid incorporation was well tolerated without an appreciable effect on toxicity profiles and secondary conformations of the synthetic peptides. The modified peptides also withstood proteolytic digestion by trypsin. The all D-amino acid peptide, i(llkk)2i (II-D), displayed superior activity against all six mycobacterial strains tested, with a 4-fold increase in selectivity index as compared with the unmodified L-amino acid peptide in broth. II-D effectively reduced the intracellular bacterial burden of both drug-susceptible and MDR clinical isolates of M. tuberculosis after 4 days of treatment. Live-cell imaging studies demonstrated that II-D permeabilizes the mycobacterial membrane, while confocal microscopy revealed that II-D not only permeates the cell membrane, but also accumulates within the cytoplasm. Conclusions Unnatural amino acid modifications not only decreased the susceptibility of peptides to proteases, but also enhanced mycobacterial selectivity

Ab initio prediction of Boron compounds arising from Borozene: Structural and electronic properties

Structure and electronic properties of two unusual boron clusters obtained by fusion of borozene rings has been studied by means of first principles calculations, based on the generalized-gradient approximation of the density functional theory, and the semiempirical tight-binding method was used for the transport calculations. The role of disorder has also been considered with single vacancies and substitutional atoms. Results show that the pure boron clusters are topologically planar and characterized by (3c-2e) bonds, which can explain, together with the aromaticity (estimated by means of NICS), the remarkable cohesive energy values obtained. Such feature makes these systems competitive with the most stable boron clusters to date. On the contrary, the introduction of impurities compromises stability and planarity in both cases. The energy gap values indicate that these clusters possess a semiconducting character, while when the larger system is considered, zero-values of the density of states are found exclusively within the HOMO-LUMO gap. Electron transport calculations within the Landauer formalism confirm these indications, showing semiconductor-like low bias differential conductance for these stuctures. Differences and similarities with Carbon clusters are highlighted in the discussion.Comment: 10 pages, 2 tables, 5 figure

Strings in AdS_4 x CP^3: finite size spectrum vs. Bethe Ansatz

We compute the first curvature corrections to the spectrum of light-cone gauge type IIA string theory that arise in the expansion of $AdS_4\times \mathbb{CP}^3$ about a plane-wave limit. The resulting spectrum is shown to match precisely, both in magnitude and degeneration that of the corresponding solutions of the all-loop Gromov--Vieira Bethe Ansatz. The one-loop dispersion relation correction is calculated for all the single oscillator states of the theory, with the level matching condition lifted. It is shown to have all logarithmic divergences cancelled and to leave only a finite exponentially suppressed contribution, as shown earlier for light bosons. We argue that there is no ambiguity in the choice of the regularization for the self-energy sum, since the regularization applied is the only one preserving unitarity. Interaction matrices in the full degenerate two-oscillator sector are calculated and the spectrum of all two light magnon oscillators is completely determined. The same finite-size corrections, at the order 1/J, where $J$ is the length of the chain, in the two-magnon sector are calculated from the all loop Bethe Ansatz. The corrections obtained by the two completely different methods coincide up to the fourth order in $\lambda' =\lambda/J^2$. We conjecture that the equivalence extends to all orders in $\lambda$ and to higher orders in 1/J.Comment: 32 pages. Published version; journal reference adde

An Efficient Distributed Intrusion Detection System in Grid Environment Using IDS

An intrusion detection system (IDS) is a device or software application that monitors network or system activities for malicious activities or policy violations and produces reports to a management station. Some systems may attempt to stop an intrusion attempt but this is neither required nor expected of a monitoring system. When aintrud erenterst hegrid system a R-LOGIN-ID is created, to a void the such kind of attacks createt he DI DS. Dis tributed Intrusion Detection System for Grid environment which hast he ability to detect the in truder in the grid environment, track and monitor his malicious activities until a thre sho ld. On cet he in trud erreac he st he thre sho ld, he is prevented from moving for ward in his malicio us activities. The grid environment and the id entification and prevention of in trusions in the distributed grid environment is to be simulated. with the help of central man ager to s ecures torage , data an alysistod etect in trusions , discovery of distri buted sens or s , and sending of al ert

Resection of Thumb Metacarpal Ewing Sarcoma and Primary Reconstruction with Non-Vascularized Osteoarticular Metatarsal Autograft

Ewing sarcoma is a primary bone malignancy that rarely occurs in the hand. Resection and reconstruction will usually result in reduced or loss of thumb function. We describe a case of successful transplantation of nonvascularized osteoarticular second metatarsal autograft following wide resection of Ewing sarcoma of first metacarpal in an 11-year-old girl. The capsule of the graft’s metatarso-phalangeal joint was repaired to achieve mobility of the joint. This enabled preservation of thumb function by a relatively simple surgical technique. Detailed surgical procedures and excellence function after 2 years following surgery are described

TOM40 Mediates Mitochondrial Dysfunction Induced by α-Synuclein Accumulation in Parkinson's Disease.

Alpha-synuclein (α-Syn) accumulation/aggregation and mitochondrial dysfunction play prominent roles in the pathology of Parkinson's disease. We have previously shown that postmortem human dopaminergic neurons from PD brains accumulate high levels of mitochondrial DNA (mtDNA) deletions. We now addressed the question, whether alterations in a component of the mitochondrial import machinery -TOM40- might contribute to the mitochondrial dysfunction and damage in PD. For this purpose, we studied levels of TOM40, mtDNA deletions, oxidative damage, energy production, and complexes of the respiratory chain in brain homogenates as well as in single neurons, using laser-capture-microdissection in transgenic mice overexpressing human wildtype α-Syn. Additionally, we used lentivirus-mediated stereotactic delivery of a component of this import machinery into mouse brain as a novel therapeutic strategy. We report here that TOM40 is significantly reduced in the brain of PD patients and in α-Syn transgenic mice. TOM40 deficits were associated with increased mtDNA deletions and oxidative DNA damage, and with decreased energy production and altered levels of complex I proteins in α-Syn transgenic mice. Lentiviral-mediated overexpression of Tom40 in α-Syn-transgenic mice brains ameliorated energy deficits as well as oxidative burden. Our results suggest that alterations in the mitochondrial protein transport machinery might contribute to mitochondrial impairment in α-Synucleinopathies

Isolated and dynamical horizons and their applications

Over the past three decades, black holes have played an important role in quantum gravity, mathematical physics, numerical relativity and gravitational wave phenomenology. However, conceptual settings and mathematical models used to discuss them have varied considerably from one area to another. Over the last five years a new, quasi-local framework was introduced to analyze diverse facets of black holes in a unified manner. In this framework, evolving black holes are modeled by dynamical horizons and black holes in equilibrium by isolated horizons. We review basic properties of these horizons and summarize applications to mathematical physics, numerical relativity and quantum gravity. This paradigm has led to significant generalizations of several results in black hole physics. Specifically, it has introduced a more physical setting for black hole thermodynamics and for black hole entropy calculations in quantum gravity; suggested a phenomenological model for hairy black holes; provided novel techniques to extract physics from numerical simulations; and led to new laws governing the dynamics of black holes in exact general relativity.Comment: 77 pages, 12 figures. Typos and references correcte

Dualities for Loop Amplitudes of N=6 Chern-Simons Matter Theory

In this paper we study the one- and two-loop corrections to the four-point amplitude of N=6 Chern-Simons matter theory. Using generalized unitarity methods we express the one- and two-loop amplitudes in terms of dual-conformal integrals. Explicit integration by using dimensional reduction gives vanishing one-loop result as expected, while the two-loop result is non-vanishing and matches with the Wilson loop computation. Furthermore, the two-loop correction takes the same form as the one-loop correction to the four-point amplitude of N=4 super Yang-Mills. We discuss possible higher loop extensions of this correspondence between the two theories. As a side result, we extend the method of dimensional reduction for three dimensions to five dimensions where dual conformal symmetry is most manifest, demonstrating significant simplification to the computation of integrals.Comment: 32 pages and 6 figures. v2: minus sign corrections, ref updated v3: Published versio

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

The empirical analysis of non-problematic video gaming and cognitive skills: a systematic review

Videogames have become one of the most popular leisure activities worldwide, including multiple game genres with different characteristics and levels of involvement required. Although a small minority of excessive players suffer detrimental consequences including impairment of several cognitive skills (e.g., inhibition, decision-making), it has also been demonstrated that playing videogames can improve different cognitive skills. Therefore, the current paper systematically reviewed the empirical studies experimentally investigating the positive impact of videogames on cognitive skills. Following a number of inclusion and exclusion criteria, a total of 32 papers were identified as empirically investigating three specific skills: taskswitching (eight studies), attentional control (22 studies), and sub-second time perception (two studies). Results demonstrated that compared to control groups, non-problematic use of videogames can lead to improved task-switching, more effective top-down attentional control and processing speed and increased sub-second time perception. Two studies highlighted the impact of gaming on cognitive skills differs depends upon game genre. The studies reviewed suggest that videogame play can have a positive impact on cognitive processes for players